CN109847071B - Increasing telomere length in cells - Google Patents
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- CN109847071B CN109847071B CN201811360814.0A CN201811360814A CN109847071B CN 109847071 B CN109847071 B CN 109847071B CN 201811360814 A CN201811360814 A CN 201811360814A CN 109847071 B CN109847071 B CN 109847071B
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Abstract
The present invention discloses a method of increasing telomere length in animal cells by administering to an animal an aqueous extract of Uncaria species. The animal may be a human, and the species of uncaria may be uncaria. Human subjects receiving a daily dose of an aqueous extract of uncaria rhynchophylla for a sufficient period of time to show an increase in telomere length relative to baseline measurements taken prior to treatment. The extract may be administered locally or systemically.
Description
Technical Field
The present application relates to a method of increasing telomere length in an animal cell. The invention is practiced by administering to the animal an aqueous extract of the species Uncaria (Uncaria).
Background
Telomeres are regions of repetitive DNA sequences at the ends of chromosomes that protect the ends of chromosomes from truncation and fusion with adjacent chromosomes. Thus, telomeres provide stability to linear DNA molecules (Greider, CW (1990) BioEssays 12(8): 363-. Telomeric TTAGGG repeats that block chromosomal ends have been shown to shorten during replicative senescence in normal cells (Harley et al (1990) Nature 345(6274): 458-460).
Telomeres are consumed during cell division, but are replenished by the action of telomerase reverse transcriptase. Human cells without telomerase gradually lose telomeric sequences due to incomplete replication. Various methods for increasing telomere length in cells are known in the art (Joeng et al (2004) Long-lived worms with Long telomeric DNA (Long life in words with Long telomeric DNA) Nature Genetics 36(6): 607-. These methods rely primarily on increasing telomerase activity. For example, studies observing normal human cells overexpressing the catalytic subunit of human telomerase have shown that increased telomerase activity leads to lengthening of telomeres (Bodnar et al, supra). Unlike the present invention, these prior art methods do not provide a method of enhancing DNA repair in combination with a method of increasing telomerase activity or increasing telomere length.
Methods for measuring telomere length are well known in the art and are described, for example, in Cawthon, RM (2002) Nucleic Acids Res.30(10): e47, Harley et al, (1990) Nature 345: 458-. Any method of measuring telomere length can be used in the present invention.
Any nucleated cell type can be used for the purpose of measuring telomere length. Lymphocytes and buccal cells are commonly used because they are readily available from patients (O' Callaghan and Fenech (2011) Biological products Online 13: 3). Peripheral leukocytes are also commonly used for telomere length assessment (Aviv et al (2011) Nucleic Acids Research 39(20): e 134). As used herein, the terms "peripheral leukocytes" and "leukocytes" are used interchangeably. Genomic DNA isolated from nucleated cell types of interest is used to measure telomere length. Methods for isolating genomic DNA are well known in the art.
U.S. patent No. 6,039,949 to Pero discloses a water-soluble extract of the species uncaria rhynchophylla, and a method of making the same. The document also discloses oral administration of the extract to rats. However, this document does not contemplate methods of lengthening telomeres or otherwise manipulating or maintaining telomere length. Also, this document does not consider measuring telomere length.
Sheng et al (2001, supra) disclose the oral administration of an aqueous extract of C-MED-100 (Uncaria tomentosa) to 12 healthy adult volunteers. The doses tested were daily doses of 250mg and 350mg for 8 weeks. A reduction in DNA damage and an increase in DNA repair was observed in both supplemented groups compared to the untreated control group. This document does not disclose a method of lengthening telomeres, nor does it contemplate measuring telomere length before and after administration of the supplement.
Lamm et al (2001, phytomedine 8(4):267-274) disclose oral administration to human volunteers
The dose was 350mg × 2 times daily for two months. Compared with the untreated control group, the test is supplemented with
The ability of the participants to respond to the 23-valent pneumococcal vaccine. Statistically significant immune enhancement was observed for those in the supplemented group. This document does not disclose a method of lengthening telomeres, nor does it contemplate measuring telomere length before and after administration of the supplement.
U.S. patent No. 7,955,626 to Pero (published 7/6/2011) discloses non-topical administration of purified alkyl or carboxyalkyl esters of quinic acid. This document discloses an aqueous extract of Uncaria (Uncaria tomentosa) and further purification of the extract by thin layer chromatography to obtain carboxyalkyl esters (CAE). The invention does not involve administration of a composition comprising quinic acid. Furthermore, the inventive method does not require the inclusion of quinic acid (either in free acid form or as a salt thereof), as the invention is particularly directed to the administration of pharmaceutical compositions comprising an effective amount of an ester, alkyl or carboxyalkyl quinic acid, meeting specified criteria. Furthermore, this document does not disclose measuring telomere length, nor does it consider increasing telomere length.
U.S. patent No. 8,372,449 (Pero, Ronald w., 12/2/2013) describes a non-topical method of administering a pharmaceutical composition comprising a purified and isolated compound selected from quinic acid and a quinic acid salt. The present invention relates to methods of enhancing a response to tumor formation and/or growth in a mammal in need thereof. The pharmaceutical composition is administered in an amount effective to inhibit TNF-alpha production or induce apoptosis in leukocytes,wherein said quinic acid and said quinic acid salt can form ammonium salts and/or chelates thereof, having a bioassay efficacy IC in HL-60 cells50About 500. mu.g/ml or less.
The disclosure shows that it is possible to use,
(aqueous extract of uncaria) is not quinic acid lactone, but quinic acid and its salts, including ammonium salts thereof. The in vivo working examples relate to oral dosing studies in mice and rats, by gavage in rats and by drinking water in mice. Due to the prolonged half-life of lymphocytes, use
Treatment of mice resulted in an increase in the number of splenocytes. Quinic Acid (QA) and its ammonium salt (QAA) are approximately equal in reversing doxorubicin-induced leukopenia in rats
As effective. The reference shows an oral daily dose of 250-
Have been shown to be effective in humans. The reference does not contemplate methods of lengthening telomeres or otherwise manipulating or maintaining telomere length. Likewise, the reference does not contemplate administration of quinic acid, a quinic acid salt, or
Telomere length is measured before or after.
It has been reported that,
(formerly known as
) The bioactive component in (A) is quinic acid lactone (USPN 6,964,784, published in 2005, 11/15). Furthermore, in vitro the bioactive agent was quinic acid lactone (USPN 8,372,448, published in 2013 on day 2 and 12), while in vivo the bioactive agent was quinic acid (USPN 8,372,449, published in 2013 on day 2 and 12).
U.S. patent No. 8,974,839 to giampaa (published 16/10/2014) discloses a multi-component supplement composition comprising an aqueous extract of uncaria, which is disclosed as a DNA repair complex. The supplement of the invention also includes a telomere maintenance complex. However, aqueous extracts of uncaria are not disclosed as telomere maintenance complexes. This reference does not contemplate methods of lengthening telomeres or otherwise manipulating telomere length. Also, this reference does not consider measuring telomere length.
U.S. patent application No. 2017/0128355 to giampaa et al (published on 5/11 2017) discloses a method of topically applying a multi-component composition comprising a water-soluble extract of a species of uncaria. The reference does not contemplate methods of lengthening telomeres or otherwise manipulating or maintaining telomere length. Also, this reference does not consider measuring telomere length.
Yu et al, U.S. patent No. 5,656,665 (announced 8/12 in 1997) discloses a method for significantly reducing skin wrinkles and reversing the effects of aging on human facial skin by topically applying quinic acid or quinilactone to the wrinkles and/or affected facial skin. A wide variety of formulations are contemplated. The working examples relate to testing various compositions by topical application to the skin in 90 volunteer subjects. The reference does not contemplate methods of lengthening telomeres or otherwise manipulating or maintaining telomere length. Also, this reference does not contemplate measuring telomere length before or after administration of quinic acid or quinlactone. This reference does not disclose the administration of an aqueous extract of uncaria rhynchophylla to a subject or cell. Furthermore, no extract of uncaria is mentioned. The reference is limited to topical application and does not contemplate other modes of administration.
U.S. patent application publication No. 2015/0338387 to Ehrenkranz (published 11/26/2015) discloses a method for monitoring and adjusting biological characteristics, such as aging. The inventive methods comprise administering a selected supplement to a subject to affect the state of a selected biological feature. The supplement may be formulated for oral administration. In a long range of possibilities, the supplement may be an extract of uncaria, and in a long range of possibilities, the biological analyte may be telomere length. This reference does not include any working examples, nor does it specifically mention the use of an extract of uncaria to increase telomere length in cells by administering the extract to a mammal. Furthermore, this reference does not specifically disclose an aqueous extract of uncaria rhynchophylla.
U.S. patent application No. 2014/0079836 to McDaniel (published 3/20 2014) discloses a method of modulating the activity of gene maintenance processes to affect the length and/or structural integrity of telomeres in living cells. Quinic acid is disclosed as an exemplary lifetime-modifying compound. The method of the invention particularly relates to contacting a cell, tissue, organ or organism with quinic acid, or an analog or derivative thereof. Quinic acid is disclosed as being naturally present in coffee beans. The disclosure contemplates lengthening telomeres, as well as modulating the activity or level of at least one telomere length maintenance gene or modulating the activity or level of telomerase. This reference does not contemplate the use of an aqueous extract of uncaria rhynchophylla for any purpose. Uncaria species (Uncaria species) are not mentioned. This reference does not specifically teach that quinic acid regulates telomere length in living cells. There is no working example on quinic acid or telomere elongation in organisms. Working examples for telomere length maintenance are provided, but these are in vitro experiments (cell culture) examining the effect of green tea extract, coffee bean extract and idebenone.
Applicants have now shown that administration of an aqueous extract of Uncaria plants (Uncaria plant) to a subject results in lengthening of telomeres.
Disclosure of Invention
The present invention relates to methods of increasing telomere length in animal cells. The invention is practiced by administering an aqueous extract of Uncaria species to an animal in an amount and for a time sufficient to increase the telomere length, and measuring the telomere length before and after administration of the extract. In a preferred embodiment, the method of the invention relates to increasing the length of telomeres in a mammalian cell, the method comprising administering an aqueous extract of uncaria species to a mammal or a mammal in need thereof in an amount and for a time sufficient to increase the length of said telomeres, and measuring the length of said telomeres before and after administration of said extract.
Accordingly, it is a first object of the present invention to provide a method of increasing telomere length in a cell, the method comprising administering to a subject an aqueous extract of Uncaria species (Uncaria species) for a time and in an amount sufficient to increase the length of telomeres in the cell of the subject.
It is another object of the present invention to provide a method of increasing telomere length in cells, the method comprising orally administering to a subject an aqueous extract of Uncaria species at a daily dose of about 200mg to about 700mg for a time sufficient to increase the length of telomeres in cells of the subject.
It is a further object of the present invention to provide a method of increasing telomere length in a cell, the method comprising administering to a subject an aqueous extract of Uncaria species for a time and in a pharmaceutically effective amount sufficient to increase the length of telomeres in a cell of the subject, wherein the Uncaria species is Uncaria (Uncaria tomentosa).
It is a further object of the present invention to provide a method of increasing telomere length in a cell, the method comprising orally administering to a subject an aqueous extract of Uncaria species at a daily dose of about 200mg to about 700mg for a time sufficient to increase the length of telomeres in the cell of the subject, wherein the Uncaria species is Uncaria (Uncaria tomentosa), wherein the time sufficient to increase the length of telomeres in the cell of the subject is at least one year, and wherein the aqueous extract comprises at least 8% carboxyalkyl ester (CAE) (weight/weight (w/w)).
It is a further object of the present invention to provide a method of increasing telomere length in a cell, the method comprising orally administering to a subject an aqueous extract of uncaria species for a time and in an amount sufficient to increase the length of telomeres in the cell of the subject, wherein the aqueous extract of uncaria species is provided in the form of a capsule, tablet, liquid or gel, and wherein the uncaria species is uncaria. The capsule, tablet, liquid or gel may be provided as a time release dosage form or a sustained release dosage form.
It is a further object of the present invention to provide a method of increasing telomere length in a cell, the method comprising orally administering to a subject an aqueous extract of uncaria species at a daily dose of about 700mg for a time sufficient to increase telomere length in a cell of the subject, wherein the uncaria species is uncaria and the subject is human.
In the present invention, there is provided a method of increasing telomere length in cells of a subject, the method comprising the steps of:
a) measuring the length of one or more telomeres of a cell sample from the subject;
b) administering to a subject an aqueous extract of Uncaria species in a pharmaceutically effective amount and for a time sufficient to increase the length of said telomeres in said cells of said subject;
c) re-measuring the length of one or more telomeres, wherein if said telomere is not lengthened, continuing administration; and
d) the method results in lengthening of the telomeres.
In another preferred embodiment, the aqueous extract is administered orally.
In another preferred embodiment, the amount of the aqueous extract is from about 200 mg/day to about 700 mg/day, and wherein the aqueous extract comprises a minimum of 8% weight/weight (w/w) carboxyalkyl ester (CAE).
In another preferred embodiment, the amount of the aqueous extract is about 700 mg/day.
In another preferred embodiment, the subject is a human.
In another preferred embodiment, the aqueous extract is formulated for delivery selected from the group consisting of: capsules, tablets, liquids, syrups, and gels.
In another preferred embodiment, the aqueous extract is formulated as a transdermal patch.
In another preferred embodiment, the aqueous extract is formulated for delivery selected from the group consisting of: capsules, tablets, liquids, syrups, and gels.
In another preferred example, the Uncaria species (Uncaria species) is Uncaria (Uncaria tomentosa).
In another preferred embodiment, the subject is a human.
In another preferred example, the uncaria species is uncaria.
In another preferred example, the time sufficient to increase the length of the telomeres in the cells of the subject is at least 6 months.
In another preferred example, the time sufficient to increase the length of the telomeres in the cells of the subject is at least 1 year.
In another preferred embodiment, the transdermal patch delivers the extract to the subject over an extended period of time.
In the present invention, there is also provided a method of increasing telomere length in cells of a subject, the method comprising the steps of:
(a) obtaining a sample of nucleated cells from a subject;
(b) measuring the length of telomeres in the nucleated cell sample;
(c) orally administering to the subject a daily dose of an effective amount of an aqueous extract of Uncaria species for a time sufficient to increase telomere length in cells of the subject;
(d) obtaining a sample of nucleated cells from the subject after the time is complete; and
(e) measuring the length of telomeres in the nucleated cell sample from the subject after the time is complete;
(f) comparing the length of the telomere before the start of the time to the length of the telomere after completion of the time; and
(g) if the telomeres are not lengthened, administration is continued.
In another preferred example, the time sufficient to increase telomere length in the cells of the subject is at least one year.
In another preferred embodiment, the nucleated cell is a leukocyte.
In another preferred embodiment, the subject is a human.
In another preferred embodiment, the measuring steps (b) and (e) are performed by quantitative polymerase chain reaction.
In another preferred example, the uncaria species is uncaria.
These and other objects, aspects and features of the present invention will be better understood from the following detailed description when read in conjunction with the embodiments described herein.
Drawings
Figure 1 is telomere length of human study participants, subject HV before and after treatment, at one and two year time points. Treatment was carried out by oral administration of an aqueous extract of Uncaria (Uncaria tomentosa) formulated into capsules at a daily dose of 700 mg. The standard curve provides the average telomere length for the general population at different ages.
Figure 2 is telomere length of human study participants, subject EL before and after treatment, at one and two year time points.
Figure 3 is telomere length of human study participants, subject DB before and after treatment, at one and two year time points.
Fig. 4 is a graph of telomere length of human study participants, subject LC before and after treatment, at one and two year time points.
Figure 5 is telomere length of human study participants, subject RC before and after treatment at one and two year time points. The subject discontinued use the second year of the study, as required by the physician
For 4 to 5 months.
Fig. 6 is telomere length of human study participants, subject LM, before and after treatment, at one and two year time points.
Fig. 7 is telomere length of KC in subjects, human study participants, before and after treatment, at one and two year time points.
Figure 8 is telomere length before and after treatment for human study participants, subject BD, at one and two year time points.
Figure 9 is telomere length of human study participants, subject MM before and after treatment, at one and two year time points. Upon request of the physician, the subject is discontinued from use
For 4 to 5 months.
Fig. 10 is a graph of telomere length before and after treatment for human study participants, subject JM, at one and two year time points.
FIG. 11 is a graph of telomere length before and after treatment in human study participants, subject LCR, at one and two year time points.
Detailed Description
Methods for administering plant extracts to animals, thereby delivering plant extracts to animal cells, are well known in the art. Standard delivery methods are considered. Thus, the botanical extract can be formulated into a delivery means such as a capsule, tablet, liquid, gel, lotion, cream or ointment to facilitate the desired dosing regimen. The plant extract can be administered orally, topically or via transdermal patch. The delivery means, in particular capsules, tablets, liquids or gels, may be provided as a time-release dosage form or an extended-release dosage form.
Methods for measuring telomere length are well known in the art and are described, for example, in Cawthon, RM (2002, supra), Harley et al (1990, supra), O' Callaghan and Fenech (2011, supra), USPN 5,489,508(West et al, published 2/6/1996) and USPN 5,741,677(Kozlowski et al, published 4/21/1998), and the examples provided herein. Quantitative polymerase chain reaction (qPCR) by Cawthon, RM (2002, supra) is a fluorescence-based assay that uses a primer pair in which each primer is designed to allow a DNA polymerase to extend from the 3' end when it repeatedly hybridizes to a telomere hexamer, but not when it hybridizes to other primers. Any method of measuring telomere length can be used in the methods of the invention.
Aqueous extracts of Uncaria (Uncaria tomentosa) used in the examples described below have been well characterized in more than 20 years of research (see, e.g., U.S. patent No. 6,039,949 to Pero, RW, published at 3.21.2000, and U.S. patent No. 8,372,449 to Pero, RW, published at 2.12.2013). Spray drying the aqueous extract on a carrier such as maltodextrin to give a commercial product containing a minimum of 8% (w/w) carboxyalkyl esters (CAE) at a concentration of 8-10% (w/w) as described in U.S. Pat. No. 8,372,449 (supra) and Sheng et al (2001, supra). The product is also called
The examples described herein use a composition containing 350mg prepared in this manner
The capsule of (1).
Has already been aligned with
A rigorous toxicology study was carried out (Sheng et al (2000) J. Ethnophoharmacology 69: 115-126). A series of single doses of the oral product to 8g/kg body weight dose in rats or 5mg/kg daily dose in human volunteers for six consecutive weeks was administered, and no acute toxicity was observed. Rats treated daily for 8 weeks with a 10-80mg/kg dose of an extract of uncaria (u.tominosa) or for 4 weeks with 160mg/kg showed no signs of acute chronic toxicity (Sheng et al, 2000, supra). In addition, the bark of uncaria is collected from the field, especially amazon rainforest. This is hot water extractionRaw materials for the process. Solvents other than water are not used in the extraction process. In addition, AC-11 has exemplary microbiological characteristics and flawless safety records for over 15 years of commercial use. Toxicology screening assays for assessing the safety of AC-11 are well known in the art (see, e.g., Hasnisa et al (2017) J.Trop.Agric. and Fd.Sci.45 (1): 111-119); zhang et al (2017) fundam. toxicol. sci.4 (2): 45-56 and parauraman, S. (2011) j. pharmacol. and Pharmacotherapeutics 2 (2): 74-79).
In a preferred embodiment, the animal is a mammal. In further embodiments, the animal is a rodent, including a mouse or a rat. In a further embodiment, the animal is a primate, including a human.
In some embodiments, the subject is a human having a disease or disorder, such as alzheimer's disease, parkinson's disease, or cancer. In other embodiments, the subject is a human exhibiting good health.
In a preferred embodiment of the method of the invention, the extract is administered orally at a dose of about 700 mg/day. In other embodiments, the dosage range is from about 200 mg/day to about 700 mg/day. In some embodiments, the daily dose is about 350 mg. In other embodiments, the daily dose is about 250 mg. Rat oral administration showed LD50>8g/kg (Sheng et al (2001) J.Ethnopharm.69: 115-26). In view of the high level of tolerance demonstrated in rats, it is contemplated to administer a dose of 10 g/day to the subject until the dose is below a level that is toxic to the subject. Similarly, although a dose of 200 mg/day is believed to be effective in increasing telomere length in the cells of the subject, doses below 200 mg/day are also contemplated to be effective in increasing telomere length in the cells of the subject when administered for a sufficient period of time. When administered for a sufficient period of time, the dosages described herein refer to an extract that contains 8-10% (w/w) CAE.
In a preferred embodiment, the time sufficient to increase telomere length in the cells of the subject is a period of up to one year. In other embodiments, the time sufficient to increase telomere length in the cells of the subject ranges from about 6 months to about 2 years. In some embodiments, the periodic administration is continued throughout the subject's lifetime, including daily administration of the uncaria extract. The duration of treatment can vary widely and still result in increased telomere length. One of ordinary skill in the art having read this disclosure can determine a pharmaceutically effective dose that results in lengthening of telomeres.
In a preferred embodiment, the frequency of administration is once daily. In other embodiments, the frequency of administration is twice daily. In other embodiments, the frequency of administration ranges from at least once daily to at least once monthly. The uncaria extract may be administered once daily, twice daily, every other day, every third day, weekly or monthly. In other embodiments, the transdermal patch is administered every other day or once a week and the extract is delivered to the subject over an extended period of time. Thus, the frequency of administration can vary widely and still result in an increase in telomere length.
In a preferred embodiment, telomeres are measured in the subject prior to administering the extract and after a time sufficient to increase telomere length in the cells of the subject. In other embodiments, samples are taken from the subject prior to administration of the uncaria extract and at various time points during treatment. The sample can be retained and telomere length can be assessed at any time after the sample is obtained. In some embodiments, the sample is collected, stored for a period of time, and then telomere length is measured after all samples are obtained from the subject.
In a preferred embodiment, the uncaria extract is formulated for oral administration, such as capsules, tablets, liquids, syrups or gels. In other embodiments, the uncaria extract is formulated for topical administration, such as a lotion, cream, ointment, or gel. In another embodiment, the uncaria extract is formulated for systemic administration as a transdermal patch.
In another preferred embodiment of the method of the invention, the species uncaria is uncaria.
Examples
The following examples illustrate aspects of the invention and provide those of ordinary skill in the art with a complete description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Rather, these non-limiting examples provide specific methods that can be used to practice the invention.
Example 1
Human telomeres are generally shortened each year in adulthood. This fact is reflected on the thick lines of each figure. A preliminary study on 11 human volunteers measured the use at time points of 1 and 2 years
Telomere length before and after treatment. Treatment was carried out by oral administration of an aqueous extract of Uncaria (Uncaria tomentosa) formulated into capsules at a daily dose of 700 mg. The extract contains 8-10% CAE (w/w). Telomere length increased in all 11 subjects, with some significant increases. Figures 1-11 provide the actual telomere length (in kilobases) and percentile scores for each subject to obtain a clear visual representation. The results are surprising and unexpected. The only exception was two subjects (RC and MM) who discontinued their use according to the physician's request
Each 4 to 5 months (fig. 5 and fig. 9). Their telomeres are the only shortened telomeres. Note that 2% to 5% loss of telomere length for a given age group during the study is normal if left untreated.
4 of 5 presented patterns with baseline scores starting well below the mean. Each score rose slightly in year 1, then soared in year 2. This finding may reflect the pairDelayed response to telomere length repair in humans with poor telomere health. While another commercial product (see USPN 7,846,904 published on 12/7/2010) suggests lengthening telomeres by increasing telomerase without repairing DNA damage, this approach is suspect in that increasing cell division capacity without reducing DNA damage is expected to increase the chance of accumulating cell mutations and epigenetic changes that may lead to cancer. Without adequate repair, cells replicate with increased accumulation of damaged DNA, which may have negative effects on health, aging, and disease.
The biological effect of (a) solves this problem, it both extends the lifetime of telomeres and cells and improves the natural DNA repair process.
The highest scoring patients changed from the mean telomere length to the 91 th percentile by year 1 and then gradually decreased to 92% by year 2.
To ensure compliance, each patient is delivered monthly
The samples selected were fairly homogeneous samples: older, health-oriented individuals, without known disease, ethical, and they pay their own telomere testing fees.
Is provided to everyone free of charge.
Whole blood was drawn from each subject at appropriate time points, processed and analyzed by spectra cell, thereby providing unbiased data collection. Nucleated leukocytes were isolated from whole blood and used to measure telomere length. Genomic DNA was isolated from leukocytes and telomere length was assessed according to qPCR method of Cawthon, RM (2002, supra). The results are surprising and unexpected. Although the statistical samples were small, a clear and robust trend appeared in the first year and continued until the second year (see table 1). The change in telomere length is typically a very slow process, and is typically a shortening process (see standard curves in fig. 1-11).
Table 1 telomere length per subject one year and two years after oral administration of an aqueous extract of Uncaria (Uncaria tomentosa) before oral administration and at 700 mg/day.
Subject RC and MM are discontinued according to physician requirements
For 4 to 5 months. Abbreviations: kb is kilobases.
| Subject of the disease | Baseline (kb) | Year 1(kb) | Year 2(kb) | Changes (kb) |
| HV | 5.68 | 6.09 | 7.24 | +1.56 |
| EL | 4.57 | 4.57 | 5.52 | +0.95 |
| DB | 7.71 | 8.16 | 8.48 | +0.77 |
| LC | 6.4 | 7.98 | 8.06 | +1.66 |
| RC | 6.02 | 6.55 | 6.36 | +0.34 |
| LM | 5.15 | 5.37 | 7.44 | +2.29 |
| KC | 6.01 | 7.06 | 7.63 | +1.62 |
| BD | 5.67 | 6.62 | 7.74 | +2.07 |
| MM | 6.89 | 6.62 | 7.11 | +0.22 |
| JM | 7.27 | 7.7 | 7.67 | +0.40 |
| LCR | 5.2 | 5.45 | 6.8 | +1.60 |
Example 2
Toxicity Studies
Is administered orally
Rats administered for up to 8 weeks at doses of 40, 80 or 160mg/kg/day did not cause any significant change in food consumption or weight gain. Single oral doses up to 8g/kg did not result in death or acute signs of toxicity. Thus, LD has been reported in rats50>8g/kg (Sheng et al (2000) J. Ethnopharm.69: 115-26). 5 to 160mg/kg per oral dose
The rats showed no significant difference in liver, kidney and spleen weight. One study did indicate that 80mg/kg was administered compared to animals receiving doxorubicin alone
The mean heart weight coefficient of rats with + doxorubicin increased significantly (4.4%) (0.386% ± 0.034 vs.0.369% ± 0.022). However, when it is to
+ doxorubicin-treated animals when compared to untreated controls,there was no significant difference in average heart weight. From 5 to 160mg/kg/day
Histopathological examination of the tissues obtained from rats treated for up to 8 weeks showed no increase in pathological changes.
Claims (22)
1. A plant of the genus Uncaria (A)Uncariaspecies) for the preparation of a medicament for increasing telomere length in cells of a subject, wherein telomere length is increased in cells of a subject by a method comprising:
a) measuring the length of one or more telomeres of a cell sample from the subject;
b) administering to the subject an aqueous extract of Uncaria species in a pharmaceutically effective amount and for a time sufficient to increase the length of said telomeres in said cells of said subject;
c) re-measuring the length of one or more telomeres, wherein if said telomere is not lengthened, continuing administration; and
d) the method results in lengthening of the telomeres,
wherein the Uncaria species is Uncaria rhynchophylla (Miq.) (Uncariatomentosa）。
2. The use of claim 1, wherein the aqueous extract is administered orally.
3. The use of claim 2, wherein the amount of the aqueous extract is from about 200 mg/day to about 700 mg/day, and wherein the aqueous extract comprises a minimum of 8% weight/weight (w/w) carboxyalkyl ester (CAE).
4. The use of claim 3, wherein the amount of said aqueous extract is about 700 mg/day.
5. The use of claim 4, wherein the subject is a human.
6. The use of claim 1, wherein said aqueous extract is formulated for delivery selected from the group consisting of: capsules, tablets, liquids and gels.
7. The use of claim 1, wherein said aqueous extract is formulated as a syrup.
8. The use of claim 1, wherein said aqueous extract is formulated as a transdermal patch.
9. The use of claim 2, wherein the aqueous extract is formulated for delivery selected from the group consisting of: capsules, tablets, liquids and gels.
10. The use of claim 2, wherein the aqueous extract is formulated as a syrup.
11. The use of claim 5, wherein the aqueous extract of Uncaria species is AC-11®。
12. The use of claim 1, wherein the subject is a human.
13. The use of claim 1, wherein the aqueous extract of uncaria species is AC-11®。
14. The use of claim 1, wherein said time sufficient to increase the length of said telomeres in said cells of said subject is at least 6 months.
15. The use of claim 1, wherein said time sufficient to increase the length of said telomeres in said cells of said subject is at least 1 year.
16. The use of claim 8, wherein said transdermal patch delivers said extract to said subject over an extended period of time.
17. Use of an aqueous extract of Uncaria species for the preparation of a medicament for increasing telomere length in cells of a subject, wherein telomere length is increased in cells of a subject by:
(a) obtaining a sample of nucleated cells from a subject;
(b) measuring the length of telomeres in the nucleated cell sample;
(c) orally administering to the subject a daily dose of an effective amount of an aqueous extract of Uncaria species for a time sufficient to increase telomere length in cells of the subject;
(d) obtaining a nucleated cell sample from the subject after the time is completed; and
(e) measuring the length of telomeres in the nucleated cell sample from the subject after the time is complete;
(f) comparing the length of the telomere before the beginning of the time to the length of the telomere after the time is completed; and
(g) if the telomeres are not lengthened, administration is continued,
wherein the Uncaria species is Uncaria rhynchophylla.
18. The use of claim 17, wherein the time sufficient to increase telomere length in the cells of the subject is at least one year.
19. The use of claim 17, wherein said nucleated cell is a leukocyte.
20. The use of claim 17, wherein the subject is a human.
21. The use of claim 17, wherein said measuring steps (b) and (e) are performed by quantitative polymerase chain reaction.
22. The use of claim 17, wherein the aqueous extract of uncaria species is AC-11®。
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| US6039949A (en) * | 1997-02-27 | 2000-03-21 | Campamed, Inc. | Method of preparation and composition of a water soluble extract of the plant species uncaria |
| CA2289531C (en) * | 1997-05-15 | 2009-09-29 | University Of Washington | Composition and methods for treating alzheimer's disease and other amyloidoses |
| EP1335738A4 (en) * | 2000-11-03 | 2004-09-08 | Proteotech Inc | Methods of isolating amyloid-inhibiting compounds and use of compounds isolated from uncaria tomentosa and related plants |
| BRPI0411856A (en) | 2003-06-23 | 2006-08-29 | Geron Corp | compositions and methods for increasing telomerase activity |
| RU2007138220A (en) * | 2005-03-16 | 2009-04-27 | Рональд В. ПЕРО (SE) | MEDICAL COMPOSITIONS OF SALTS, CHELATES AND / OR FREE ACIDS, ORGANIC ACIDS WITH ALPHA HYDROXYL AND RELATED PROCESSES AND METHODS |
| US8372488B2 (en) * | 2006-05-01 | 2013-02-12 | General Electric Company | Methods and apparatus for thermal barrier coatings with improved overall thermal insulation characteristics |
| CA2690004C (en) * | 2007-06-04 | 2018-01-23 | Ben-Gurion University Of The Negev Research And Development Authority | Tri-aryl compounds and compositions comprising the same |
| US8029830B2 (en) * | 2008-04-18 | 2011-10-04 | Nuvocare Health Services Inc. | Composition and method for promoting internal health and external appearance |
| ES2656958T3 (en) * | 2011-03-28 | 2018-03-01 | Geron Corporation | Measurement of telomere length in samples fixed in formalin, embedded in paraffin (FFPE) by quantitative PCR |
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| EP2934558A4 (en) * | 2012-12-21 | 2016-07-27 | Joel R L Ehrenkranz | Supplements and monitoring systems for dosing of the supplements |
| WO2014153356A1 (en) * | 2013-03-18 | 2014-09-25 | Life Science Institute, Llc | An in vivo intracellular reprogramming composition and method of making and using same |
| US9968546B2 (en) | 2015-11-10 | 2018-05-15 | Vincent C Giampapa | Topical composition for skin treatment to reduce lines and wrinkles of the face and body using a dual DNA repair mechanism to address damage caused by aging and ultra-violet induced damage to the skin with combination of skin turgor enhancement compounds |
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